Elephants: Large, Long-Living and Less Prone to Cancer

The argument of Dr. Peto, a University of Oxford statistician, was beguilingly simple. Every time a cell divides, there’s a small chance it will gain a mutation that speeds its growth. Cells that accumulate several of these mutations may become cancerous. The bigger an animal is, the more cells it has, and the longer an animal lives, the more times its cells divide. We humans undergo about 10,000 times as many cell divisions as mice — and thus should be far more likely to get cancer.

A number of scientists have speculated that large, long-lived animals must evolve extra cancer-fighting weapons. And if that’s true, they reason, then the biggest, longest-lived animals should have an especially big arsenal. Otherwise, these species would go extinct.

“Every baby elephant should be dropping dead of colon cancer at age 3,” said Dr. Joshua D. Schiffman, a pediatric oncologist at the Huntsman Cancer Institute at the University of Utah.

Writing Thursday in JAMA, Dr. Schiffman and his colleagues report that elephants appear to be exceptional cancer fighters, using a special set of proteins to kill damaged cells.

Working independently, Vincent J. Lynch, an evolutionary biologist at the University of Chicago, and his colleagues have come to the same conclusion. Those researchers posted a draft of their paper on Wednesday on the bioRxiv server. It is currently in review at the journal eLife.

Dr. Schiffman and his colleagues found in their research that elephants had a remarkably low rate of cancer. They reviewed zoo records on the deaths of 644 elephants and found that less than 5 percent died of cancer. By contrast, 11 percent to 25 percent of humans die of cancer — despite the fact that elephants can weigh a hundred times as much as we do.

To understand the elephants’ defenses, the scientists investigated a gene that is crucial for preventing cancer, called p53. The protein encoded by the gene monitors cells for damage to the DNA they contain. In some cases, it prompts the cells to repair the genes. In other cases, p53 stops cells from dividing further. And in still other cases, it even causes the cells to commit suicide.

One sign of how important p53 is for fighting cancer is what happens to people born with a defective copy of the gene. This condition, known as Li-Fraumeni syndrome, creates a lifetime risk of cancer of more than 90 percent. Many people with Li-Fraumeni syndrome get cancers as children and can have several types of cancer over their lifetimes.

Dr. Schiffman and his colleagues found that elephants had evolved new copies of the p53 gene. While humans have only one pair of p53 genes, the scientists identified 20 pairs in elephants.

Dr. Lynch and his colleagues also found these extra genes. To trace their evolution, the researchers made a large-scale comparison of elephants to other mammal species — including extinct relatives like woolly mammoths and mastodons whose DNA remains in their fossils.

The small ancestors of elephants, Dr. Lynch and his colleagues found, had only one pair of functional p53, like other mammals. But as they evolved to bigger sizes, they steadily evolved extra copies of p53.

“Whatever’s going on is special to the elephant lineage,” Dr. Lynch said.

To see whether these extra copies of p53 made a difference in fighting cancer, both teams ran experiments on elephant cells. Dr. Schiffman and his colleagues bombarded elephant cells with radiation and DNA-damaging chemicals, while Dr. Lynch’s team used chemicals and ultraviolet rays.

In all these cases, the elephant cells responded in the same way: Instead of trying to repair the damage, they simply committed suicide. Dr. Schiffman saw this response as a unique — and very effective — way to block cancer. “It’s almost as if they said, ‘We’re elephants — we’ve got plenty more cells where those came from,’ ” Dr. Schiffman said.

Patricia Muller, an oncologist at the MRC Toxicology Unit at the University of Leicester who was not involved in the studies, said the results, though compelling, didn’t firmly establish exactly how elephants use p53 to fight cancer. One possibility is that the extra copies don’t actually cause cells to commit suicide. Instead, they may act as decoys for enzymes that destroy p53 proteins. As a result, elephants can have higher levels of p53 than other animals. “All in all, it’s interesting, but the mechanism needs to be properly investigated,” she said.

Dr. Muller said it was especially important to understand precisely how elephants fight cancer before trying to mimic their strategies with drugs for humans. Experiments in which mice get extra amounts of p53 have shown that the molecule has a downside: It can accelerate aging. “It has to be kept under tight control,” Dr. Muller said.

Dr. Schiffman is now investigating how to translate the new findings on elephants into cancer treatments for people. But he said it would be useful to look at other big or long-lived animals as well. Naked mole rats, for example, live up to 30 years without ever getting cancer. One weapon they use is a protein that arrests the growth of fast-dividing cells. It senses when these cells bump into other cells and brings their division to a halt.

That is an entirely different solution from the one elephants appear to have evolved. And elephants are the only animals yet found that fight cancer with extra p53 genes. So Dr. Schiffman speculates that parrots, tortoises and whales may all have special longevity tactics of their own.

“The war on cancer was going on long before there were humans,” he said. “So let’s look at nature’s strategies.”